the importance of the plummer-vinson synlqrome in … · lower incidence of plummer-vinson syndrome...

POSTORAD. MED. j. (I96I), 37, 523

THE IMPORTANCE OF THEPLUMMER-VINSON SYNLqROME IN THE

AETIOLOGY OF CARCINOMA OF THE UPPERGASTRO-INTESTINAL TRACT

J. McK. WArrS, M.B., B.S.Registrar, Unit ersity Department of Surgery, Alfred Hospital, Melbourne, Australia

ON May 2, I9I9, at the Summer Congress of theLaryngological Section of the Royal Society ofMedicine, two British laryngologists, D. R.Paterson and A. Brown-Kelly, independently readpapers describing a quite specific type of dysphagiaoccurring usually in middle-aged women. Thedysphagia, although sometimes of sudden onset,was usually of long standing and was referred tothe level of the larynx. Both Paterson and Brown-Kelly remarked on the commonly associatedatrophy of the mucosal lining of the upper gastro-intestinal tract. The lesions observed were fis-sures at the angles of the mouth, atrophic glossitis,pale smooth pharyngeal mucous membrane andstrictures or web-like deformities at the pharyngo-esophageal junction.Brown-Kelly, in his contribution, made passing

mention of a history of anemia in some of hispatients. Two years later Porter P. Vinson (1922),this time a physician at the Mayo Clinic, pub-lished a paper on what he called ' HystericalDysphagia'. This was primarily an affliction ofwomen and it was noticeable that 37 of his 63patients had hamoglobin values of less than 6o%.It has since become reasonably evident that hewas describing precisely the same clinical con-dition as were his British contemporaries; whichmakes it all the more surprising that he failed tonote any of the abnormal changes on endoscopyof the pharynx or lesions of the mouth and tongueto which Paterson and Brown-Kelly had paid somuch attention. This absence of any evidentorganic disease in the upper food passages ledhim to the conclusion that the dysphagia was anhysterical manifestation. This view was not sup-ported by Paterson and Brown-Kelly, who con-sidered that the dysphagia was due to spasmconsequent on the local anatomical changespresent at the site of obstruction.

Jt was on the basis of this communication alonethat Vinson has come to enjoy eponymous dis-

tinction. More fortunate still is Plummer, aphysician colleague at the Mayo Clinic, whodoes not seem to have made any literary contri-bution on this topic and to whose interest in thecondition Vinson only made passing reference inhis paper. In the discussion which followed thepresentation of Vinson's paper it was suggestedthat ' because of the fact that no other clinic hasrecognized this disease, it seems only fair thatDr. Vinson's name should be given to thisdisease'. However, not all the audience were sobenevolent, for when Dr. S. H. Boyer, of Duluth,remarked, ' the multiplicity of personal namesfor disease is wrong; let us not add to this butlet us distinguish the doctor (Vinson) in someother manner', we are informed that his commentwas greeted by applause. It must, none the less,be admitted that however strong may be ourclaim for the British contributors on the score ofpriority, we will find it hard to win a place forPaterson and Brown-Kelly. Plummer-Vinsonsyndrome it is, and so it is likely to remain.

It is largely to the contributions of the Scandi-navian and particularly of the Swedish writersthat we are indebted for our more completeunderstanding of this disease, if disease it deservesto be called. It is evident that there is, inSweden, a remarkable incidence of this conditionamongst the female population although in theother Scandinavian countries and in Great Britain,North America and Australia it is much lesscommon.The disease is almost always confined to

females of middle age (contrast Figs. i and 2).The dysphagia, usually referred to the level ofthe larynx, is often of many year's duration andinsidiously progressive. There is often completeedentia, a tight and smooth facial skin, a smallmouth fissured or scarred at the angles, andfingernails which are usually brittle and some-times spoon-shaped (Fig. i). We note that

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POSTGRADUATE MEDICAL JOURNAL

FIG. i.-Severe koilonychia andirregularity of the nails in amale patient with Plummer-Vinson Syndrome.

*FIG. 2.-(Same patient as Fig. I.)After iron therapy for one year,the nails have become normal.

*Figujres x and 2 reproduced withthe kind permission of Pro-fessor Jacobson of the Radium-hemmet, Stockholm.

similar changes are seldom described in the toe-nails, nor have we observed them. The buccalmucosa is pale, atrophic and often the seat ofleukoplakia; the tongue is atrophic and red(Fig. 3). Similar changes are evident in thepharynx and crsophagus and are often associatedwith fibrous bands or web-like strictures in thelower pharynx or upper cesophagus (Fig. 4).Atrophy of the gastric mucosa is often presentand usually associated with achlorhydria. Thespleen is palpable in about 20% of cases. Many

patients have an associated hypochromic micro-cytic anaemia, but its absence is not uncommon.This is the clinical picture presented by a

patient with severe long-standing disease. Butit is important to remember that the clinicalfeatures are often much less evident. Most im-portant of all we have now come to recognize thatanemia is very often not in evidence.

It is now agreed that the Plummer-Vinsonsyndrome is the sequel of a long-standing depletionof body iron stores and there are two features of

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WATTS: The Importance of the Plummer-Vinson Syndrome

FIG. 3.-(Case 5) Atrophic mucosaand superficial ulceration of thetongue. The area of scarringon the left side of the dorsumof the tongue was the site of asquamous cell carcinoma treatedby radon seed implantationthree months prevoiusly

FIG. 4.-A thin fold in the uppercesophagus, arising anteriorlyand stretching across the lumen-a typical web.

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the condition which are usually regarded as beingessential for its diagnosis. They are, firstly, dys-phagia associated with the characteristic mucosallesions, and secondly, evidence of dimini-hedbody iron stores usually associated with low serumiron values and absence of stainable iron in, thebone-narrow. It was the constant presence ofthese two features that led Waldenstrom andKjellberg (I939) to introduce the term 'sidero-penic dysphagia' to describe the condition; this-is a much' more informative title and its usedodges the controversy in the eponymous descrip-tion of this syndrome that has taken place overthe years. In a recent review of Swedish cases,however, Wynder and Fryer (I958) state thatmany female patients, having the classical clinicalstigmata of the Plummer-Vinson syndrome withor without cancer, have normal serum iron andhiemoglobin values when first seen. This some-what surprising observation they attribute tothe fall in iron requirements that follow thecessation of menstruation, the persisting tissuechanges being presumably irreversible.

It was probably Logan Turner, of Edinburgh,who was the first to observe, in 1913, the neo-plastic potential of the mucosal lesions seen inthis syndrome. He described 68 cases of ma-lignant disease of the esophagus and remarkedon the greater female incidence of carcinoma atthe upper end' compared with other levels in the(esophagus. He also commented on the oftenprolonged history of dysphagia in many of thesewomen with carcinoma, and stated: 'These casessufficiently illustrate the period over which symp-toms produced by undoubted malignancy of theesophagus may continue'. The average durationof the dysphagia in Logan Turner's female patientswith hypopharyngeal carcinoma was five years.By 1920 Logan Turner had extended his observa-tions to I40 cases of cesophageal carcinoma, 98 ofwhom were hypopharyngeal. Of these 98, no lessthan 85 occurred in females. Whereas, in males,the average duration of the dysphagia was but afew months,' the dysphagia in the females had insome cases been present for many years. Beingby then aware of the writings of Paterson andBrown-Kelly, Logan Turner wrote: 'In mostwomen whose period of symptoms is unusuallyprolonged, it is possible that a condition mayexist which favours tumour development and isthe cause of the obstruction in the earlier stagesof the history'. Because of these observations,there seems little doubt that many of LoganTurner's patients had suffered from the Plummer-Vinson syndrome or sideropenic dysphagia.Paterson, in I919, had remarked on ... . the notinfrequent supervention in such cases of malignantdisease at the mouth of the gullet', and Brown-

Kelly had noted a striking female sex preponder-ance in his cases of hypopharyngeal carcinoma.

It had thus become clearly apparent by thistime that patients with the Plummer-Vinson syn-drome often developed hypopharyngeal or, as itis more often called, post-cricoid carcinoma.

However, it was not until 1936 that H. E.Ahlbom, from observations at the Radiumhemmetin Stockholm, produced convincing evidence ofthe development of cancer of the hypopharynx inpatients with the Plummer-Vinson syndrome.When in 1937 Ahlbom examined the records of

all the women treated at the Radiumhemmet formeso- and hypopharyngeal carcinoma from 193Ito 1936, he found that the Plummer-Vinson syn-drome was present in no less than go%. But hewas also able to show from his experience (andthis is an important fact which is often over-looked) that the risk of cancer developing was notconfined to the post-cricoid area but affected alsothe buccal mucosa, tongue, and all levels of thecesophagus.The incidence of the Plummer-Vinson syn-

drome in Australia is probably little differentfrom that which obtains in the United Kingdomor in the North American continent and, largelydue to its infrequency, figures for its incidenceare not readily obtainable. We have, however,been able to lay hands on a limited number offigures of the incidence of upper gastro-intestinaltract carcinoma reported at the Central CancerRegistry, Melbourne, in the years 1950 to 1954,and to compare them with the number reportedfrom hospitals in Swedeni, Denmark, the UnitedKingdom and the United States during the sameperiod (Table I).The figures for Melbourne reveal approxi-

mately the same sex incidence as was observed inDenmark, the United Kingdom and NorthAmerica; in contrast are the figures for Swedenwhich reveal a striking female incidence, especiallyat hypopharyngeal level.

Vidboek, in 1944, reviewed I,3I3 cases ofupper alimentary tract carcinoma in Denmark.The incidence of carcinoma of the pharynx andcesophagus in females was only half that ofSwedish women and this he attributed to thelower incidence of Plummer-Vinson syndrome inDanish as compared with Swedish women. Onlysix of his patients, all female, had evidence ofthis syndrome.There is, therefore, reasonably convincing evi-

dence that in -women the Plummer-Vinson syn-drome is an important xtiological factor in thecausation of cancer of the mouth, pharynx and(esophagus. Certainly the incidence of cancer atthese sites in women parallels fairly closely the

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TABLE INUMBER OF CANCER PATIENTS AND P-ERCENTAGE OF WOMEN WITH CANCER, BY SITE, AT HOSPITALS IN AUSTRALIA, SWEDEN

DENMARK, ENGLAND AND THE UNITED STATE DURING 1950-1954Site Australia Sweden Denmark England United States

Melbourne Radiumhemmet Radium Centre Royal Marsden Memorial Centre

No. % No. % No. % No. % No. %Patients Women Patients Women Patients Women Patients Women Patients Women

Lip 334 I9 249 9 200 12 33 15 219 7

Buccal Mucosa 9 22 74 5 1 34 35 I6 25 8 37

Gingiva 13 3I 64 47 34 53 13 38 207 26

Palate 26 27 28 50 27 37 31 19 i6o 23

Tongue 94 27 I64 45 99 41 82 22 549 30

Tonsil 36 17 31 29 29 24 40 25 178 I6

Naso-pharynx 14 50 II3 42 31 26 72 25 154 27

Hypo-pharynx 49 35 157 57 6o I8 II8 30 349 8

CEsophagus 176 30 259 39 213 28 83 32 308 i6

(Based on Wynder, Hultberg, Jacobsson and Bross (1957))

frequency of the Plummer-Vinson syndrome, andthis is strikingly borne out by the Swedish figures.

In spite of the relative infrequency of thissyndrome in Australia we have-within recent timestreated patients suffering from cancer of the uppergastro-intestinal tract, each of whom had some orall of the stigmata of the Plummer-Vinsonsyndrome.

It seemed to us not inappropriate to give ashort account of these five cases in an attempt tounderline the importance of this syndrome as antetiological factor in the causation of mouth cancerand the need to be constantly on the look-out forthis complication in any patient with a longhistory of dysphagia with or without iron-deficiency anaTmia.Case ReportsCASE I-Carcinoma cf the Alveolus, Tongue, Palate,Hypopharynx

Mrs. C. H., an English migrant aged 65 years, wasadmitted to the Alfred Hospital in December I960,under the care of Dr. J. Stubbe.

Five years before, whilst an inpatient in the LondonHospital, she had complained of dysphagia and ulcersin the mouth of ten years duration. She was then foundto have the characteristic facies of the Plummer VinsonSyndrome and her fingernails were flat and ridged.There was an ulcerating tumour involving both the floorof the mouth and the left mandible which was proven onbiopsy to be an eatly infiltrating squamous cell car-cinoma. Because of an extensive tissue reaction whichdeveloped before a course of radiotherapy could becompleted, surgical excision of the tumour and left halfof the mandible was performed.

Apart from continuing mild dysphagia she had re-

mained well following this operation but was admittedto the Alfred Hospital with a short history of weakness,dyspncea, weight loss and increasing dysphagia.

She was pale and thin and had scarring at the angles ofthe mouth and leukoplakia of both upper and lower lips.Her operation scar was well healed and there was nohint of local or cervical lymph node recurrence. Thebuccal mucosa was pale and atrophic and the gumsedentulous. The tongue was atrophic, bled easily andwas surmounted by multiple white flat plaques 3 to 4mm. in diameter (Fig. 5). There was an irregularpenetrating ulcer I cm. in diameter on the soft palate.Her fingernails were brittle and ridged but not spoon-

FIG. 5. (Case I) Multiple raised plaques on the tonguewhich, on biopsy, proved to be squamous cellcarcinoma.

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shaped; the spleen was not palpable but the liver wasenlarged and irregular.

Investigations. Hemoglobin 8 g./ioo ml.; blood film,hypochromic anaemia; serum iron, 25L9g.10oo ml.;stools positive for occult blood. CEsophagoscopy (Mr.G. Stirling): at I4 cm. from the alveolar margin therewas a friable, fungating annular tumour preventing entryto the (esophagus. Biopsies of the lesions on thetongue, palate and hypopharynx showed well differ-entiated squamous cell carcinoma. Biopsy of thebuccal mucosa showed atrophy with submucosalinflammatory cell infiltration.A palliative course of radiotherapy was prescribed.

CASE 2-Carcinoma of the HypopharynxMrs. E. B. aged 65 years was admitted to the Royal

Melbourne Hospital on April 14, I960, under the careof Professor R. R. H. Lovell.From the age of 40 years or thereabouts she had

experienced difficulty in swallowing, solid food appearingto stick at the level of the supra-sternal notch. Duringthe previous year, she had become progressively moretired and short of breath on exertion. The dysphagiahad increased in severity in the past three weeks.

Examination revealed a thin, pale woman withkoilonychia and brittle nails. She was edentulous andhad a red atrophic tongue and cracking at the anglesof her mouth. The spleen was palpable.

Investigations. Hmmoglobin 5.9 g./ioo ml.; bloodfilm, erythrocytes hypochromic with anisocytosis;colour index 0.46; serum iron i6 tLg./ioo ml.; occultblood negative; bone marrow, hyperplastic with nostainable iron. X-ray: Barium swallow demonstratedan extensive irregular tumour of the hypopharynxextending into the upper cesophagus. This on biopsyproved to be a squamous cell carcinoma and a sectiontaken from the mucosa adjacent to the lesion showedquite striking hyperkeratotic changes.

Operative treatment was considered inadvisablebecause of her poor general condition and she died twoweeks after admission despite blood transfusion.Autopsy revealed an extensive carcinoma of the hypo-

pharynx extending into the upper cesophagus (Fig. 6).There were metastases present in adjacent lymph nodesand in the liver.

CASE 3-Carcinoma of the Buccal MucosaMrs. J. B., aged 63 years, was admitted to the Royal

Melbourne Hospital on October I9, I956, under the careof Professor M. R. Ewing. For as long as she couldremember she had found difficulty in swallowing solidfoods. For one month she had suffered with tirednessand a painful tongue and recently a small ulcer hadappeared near her lower gum.She was a thin edentulous woman with atrophic

glossitis and some small areas of leukoplakia on thelower alveolus. She had a firm, raised circular ulceratedlesion 3 cm. in diameter in the right lower gingivo-buccal sulcus encroaching on the right alveolus (Fig. 7).A single hard lymph node I cm. in diameter was palpablein the right submandibular region.

Investigations. Hmmoglobin I3 g./ioo ml.; bloodfilm normal; W.R. negative. X-ray: Barium swallowrevealed a web in the lower cervical (esophagus. Biopsyof lesion: squamous cell carcinoma of the buccalmucosa.On October Io, 1956, an excision of this lesion with the

right half of the mandible and a right-sided block dis-section of the neck was performed. She remained welluntil January, 1957, when a left-sided submandibular

FIG. 6.-(Case 2) Autopsy specimen showing an ex-tensive carcinoma of the hypopharynx and acarcinoma of the upper (esophagus.

recurrence necessitated a left-sided block dissection ofthe neck.Ten months after the original, excision she again

presented with a recurrence in the right parotid gland.A course of deep X-ray therapy was commenced but shedeteriorated and died on September I, 1957.Autopsy revealed secondary squamous cell carcinoma

in the right parotid gland.

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FIG. 7.-(Case 3) Carcinoma of the buccal mucosa.

CASE 4-Carcinoma of the ([EsophagusMrs. M. M., aged 6o years, was admitted to the

Alfred Hospital on March i, 1957, under the care ofProfessor M. R. Ewing. For 17 years she had beenunable to eat solid foods because of obstruction toswallowing at the level of the manubrium sterni. Forfive weeks she had suffered from lower sternal dis-comfort on eating, pain under the left costal margin,regurgitant vomiting, anorexia and loss of weight.Some years previously she had been given a bloodtransfusion because of anemia.

Examination revealed a thin, pale, edentulous womanwith a small mouth with angular scarring. She had araw, smooth tongue and koilonychia.

Investigations. Hamoglobin 9.7 g./ioo ml.; bloodfilm, hypochromic red cells with anisocytosis; serumiron 35 9g./Ioo ml. X-ray: Barium swallow revealedpartial obstruction to the passage of barium due to a webat the level of the sixth cervical vertebra. There wasalso dilatation of the middle third of the cesophagus andan irregular stricture in the lower third. CEsophagoscopy(Mr. K. N. Morris): The entrance to the cesophagus wasdifficult to identify and a lesion in the nature of a webwas ruptured before entering the cesophagus. At 35cm. a fungating tumour was visualized. Biopsy of thislesion proved it to be a well differentiated squamous cellcarcinoma.On March 21, I960, a partial cesophago-gastrectomy

was performed by Mr. K. N. Morris. The resectedspecimen revealed an extensive squamous cell carcinomaof the lower third of the cesophagus without spread toadjacent lymph nodes.Now three and a half years later she remains well

despite some mild residual dysphagia.

CASE 5-Carcinoma of the TongueMrs. E. S., aged 64 years, was admitted to the Alfred

Hospital on March 3, I960, under Dr. J. McLean. Forthe past I7 years she had suffered with dysphagia,recently increasing in severity. Over this period atypical Raynaud's phenomenon had affected her handsand feet on exposure to cold' She had suffered formany years from anemia resistant to treatment withVitamin B12. Over the previous year she had sufferedfrom anorexia, mild loss of weight and a painful tongue.

Examination revealed a well nourished woman withsclerodactyly, brittle nails and tight, smooth facial skin.There was scarring at the angles of the mouth and a rawsmooth tongue with shallow and non-indurated ulcera-tion on the left side of the dorsum measuring i cm. by2 cm. in diameter (Fig. 3). There was no palpablecervical lymph nodes.

Investigations. Haemoglobin I3.8 g./ioo ml.; bloodfilm normal; serum iron 40 ±g./io00 ml.; Wassermannnegative; Schilling test normal; Histamine test meal,achlorhydria; stools negative for occult blood. X-ray:barium swallow revealed a small web in the post cricoidregion. There was also dilatation of the lower third ofthe cesophagus and a stricture at the lower end.CEsophagoscopy: fibrous stricture 5 mm. in diameterdilated at pharyngo-cesophageal junction. Benignstricture at lower end of cesophagus. Gastric mucosaatrophic. Biopsy of ulcer on tongue: well differentiatedsquamous cell carcinoma.The dysphagia was subsequently relieved by the

regular passage of bougies. In June, I960, radon seedswere implanted into the tongue lesion after she hadrefused any major operative procedure.

DiscussionThe important points that now emerge for

discussion are:(a) What is the itiology of this condition ?(b) What is the nature of the lesions in the

upper alimentary tract ?(c) Is the condition preventable or are the

established lesions reversible ?

(a) What is the &etiology of this condition ?As in the case with many other disease com-

plexes, controversy has existed over the truectiology of this syndrome.

Streptococcal infection (Hurst, 1926), tertiarysyphilis, vitamin deficiency, hysteria (Vinson,1922), and 'gastric inadequacy' (Suzman, I933)have all, at some time, been suggested as possiblecauses. Dysphagia was once considered to be theprimary factor, the resulting inadequate oralintake being held responsible for the secondarydeficiencies. The passage of cesophageal bougiesalone, however, 'although it may be effective in therelief of dysphagia and in the amount and varietyof oral intake, has been shown to lead to little orno improvement in the condition (Johnson, 193I).The commonly associated achlorhydria and gastricatrophy led to the suggestion that the primarydefect was that of 'gastric inadequacy'. It has,however, subsequently been shown that thepresence of acid in the stomach is only of minor

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importance in iron absorption. Nevertheless, itmay assume greater importance when the iron inthe diet is only just sufficient for daily needs.Witts (I93I) treated his patients with liver, hydro-chloric acid and multiple vitamins and found thatthe lesions did not improve. This was in directcontrast to the rapid response with iron therapy.Treatment with riboflavine alone has been foundto improve only the oral fissures (Hurst, 1926).

There is now little doubt that the degenerativechanges in the mucous membranes of the uppergastro-intestinal tract associated with the Plum-mer-Vinson syndrome are primarily caused by aprolonged iron deficiency. Most of the evidencefor this has been of an indirect nature, that is theobserved resolution of many of the lesions withiron administration (Witts, I93I; Suzman, 1933;Andersson, I955; Waldenstrom, 1938). Vinson(1922) had treated his dysphagic female patientswith iron, arsenic, and cesophageal bouginage andremarked on the rapid improvement in the symp-toms and blood picture. There is good evidencethat iron usually produces a rapid resolution ofthe nail and epithelial changes (Figs. I, 2), butless often is there any lessening of the dysphagia.

It is observed that this syndrome occurs almostalways in females and rarely in males. This isreadily explained by the increased iron require-ments of the female during menstruation, preg-nancy and lactation. Many of these women liveon a diet which is marginal in iron content andthe increased requirements during reproductivelife predispose to the development of iron defi-ciency. Since I938 the Swedish Public HealthService has sponsored the fortification of whiteflour with iron and vitamin B, and '... it is nowa widely held clinical impression in Sweden thatPlummer-Vinson syndrome is becoming a pro-gressively rarer entity ' (Wynder and Fryer, 1958).

It is believed that iron deficiency produces ageneralized disturbance affecting the whole or-ganism and that the deficiency is most evident inthe tissues where cells are constantly being re-generated (Demulder, I958). Changes are readilyobserved, for example, in the bone-marrow (dis-turbed cell maturation), skin and its appendages(koilonychia, smooth facial skin with oral angularfissures), and mucous membranes (buccal cavity,-tongue, pharynx, cesophagus, stomach). Thesmall intestinal mucosa, where mitosis is so active,however is usually not affected (Rawson andRosenthal, I960).

Iron is present in the body chiefly as hamo-globin and myoglobin, but is also an essentialcomponent of the intracellular enzymes catalase,peroxidase and the cytochromes. All these en-zymes play an essential role in the transport andutilization of oxygen for energy requirements.

Beutler (1957, 1959) has shown experimentallythat, in rats made iron deficient by bleeding,specific intracellular iron-containing enzyme defi-ciencies occur in some organs. These enzyme de-ficiencies have not been shown to occur in thealtered mucosal cells in human patients withchronic iron deficiency, but metabolic studies ofexcised 'precancerous' leukoplakic mucosa sug-gest an abnormal pattern of oxidative mechanismbefore carcinoma develops (Weisberger, 1957).

If these deficiencies of iron-containing enzymesdo in fact occur, the subsequent neoplastic changein the mucosa may be explained by the theory ofWarburg (1956), who states that the first phase inthe origin of a carcinoma cell is the irreversibleinjuring of respiration followed by a long strugglefor existence of injured cells, those survivingreplacing the lost respiration energy by fermenta-tion energy and, in so doing, becoming de-differentiated to a neoplastic cell.

(b) What is the nature of the lesions in the upperalimentary tract ?The microscopic features of the atrophic mucous

membranes seen in this disease were first describedby Paterson (I919) and later by Suzman (I933).

In general, all the epithelium from the mouth tothe lower cesophagus is. atrophic but, in manyareas, shows evidence of increased cellular activityin the basal layers with' superficial hyperkeratosisor leukoplakia (Figs. 8, 9) (similar to the skinlesion seen after initial applications of a car-cinogen).The tongue mucosa is usually smooth and

devoid of papilke (Fig. 3). Throughout the areasof atrophic mucosa there is submucosal infiltra-tion with inflammatory cells. In the cesophagusthis infiltration often extends into poorlydeveloped muscle coats 'which are often partlyreplaced by connective tissue (Fig. 8). In addi-tion, further changes commonly occur in thelower pharynx or upper cesophagus. Most fre-quently this'is the characteristic and often radio-logically demonstrable web, a thin fold usuallyarising anteriorly and stretching a variabledistance across the cesophageal lumen (Fig. 4).Hoover (1935) biopsied these webs and foundthem to be composed of two mucous membranelayers with minimal intervening fibrous tissue.The obstructing lesion is often more extensive-either a narrow circular constriction of the lumenor rarely an elongated cesophageal stricture.There is commonly present an associated atrophyof the gastric mucosa with submucosal cellularinfiltration. However, the small intestine showsno macroscopic or microscopic changes (Rawsonand Rosenthal, I960).The neoplastic changes that commonly arise

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FIG. 8.-(Case 4) Biopsy of the esophagus. Leukoplakia of the oesophageal mucosa and submucousinfiltration with inflammatory cells extending into the muscle coat. ( x 120)

FIG. 9.-Biopsy of buccal mucosa in Plummer-Vinson Syndrome. Leukoplakia of the mucousmembrane. Submucous inflammatory cell infiltration. (X 170)

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in the mucosa at any level from the mouth to thelower cesophagus are stated to occur in approxi-mately io% of patients with established Plummer-Vinson syndrome (Wynder, Hultberg, Jacobssonand Bross, I957), most commonly at hypopharyn-geal level but sometimes simultaneously atmultiple sites (as in Case i). The carcinomadeveloped is always of squamous-cell variety butwith varying degrees of differentiation.

After a study of patients developing carcinomain association with web and stricture formation,Lindvall (I953) concluded that malignant de-generation did not occur at the site of thesestructural changes but in areas adjacent to them.

(c) Is the condition preventable or are the establishedlesions reversible ?Many writers have commented on the reversi-

bility of many of the lesions of Pummer-Vinsonsyndrome following the administration of iron.If anaemia is present there is an immediatehaematological response-the fingernails becomenormal (Figs. I, 2) and even the atrophic lingualand buccal mucosa may be restored to normal.The commonly present achlorhydria, especially

in older women, is not reversible (Lancet, I960).Lees and Rosenthal (1958) carried out gastricbiopsy before and after correction of the bloodpicture with iron in patients with iron deficiencyanwemia and found that the gastric mucosal lesionsof infiltration and atrophy did not improve, andin some cases progressed.

Dysphagia may be improved following theadministration of iron even without cesophagoscopyor bouginage but, if any radiological changes arepresent in the cesophagus, these usually persist.

However, it is a common observation thatsomewhere in the course of the disease the charac-teristic mucosal lesions become irreversible, evenwith prolonged treatment. It is probable then,that only in the early stages of the disease whenthe epithelial lesions are reversible, can therapywith iron prevent the later malignant changes.Weisberger (I957) stated that the treatment of theanaemia in I8 cases with Plummer-Vinson syn-dome had no effect on the eventual developmentof carcinoma. Also, of eight patients with thissyndrome observed by Lindvall (I953) and knownto have had previous iron therapy, seven de-veloped carcinoma at some later stage in thedisease.We may then argue that a prolonged iron

deficiency 'conditions' the mucosa of the uppergastro-intestinal tract producing a neoplasticpotential which at some stage becomes irre-versible. The prevention of this irreversiblechange would then depend ideally on the pre-vention of iron deficiency or, if iron deficiency

occurs, on its early diagnosis and on the con-tinued replenishment of the depleted iron stores.There is as yet no evidence to prove whether ornot the incidence of subsequent neoplasia can beinfluenced by adequate iron therapy once irre-versible, but still benign changes have occurred.Therefore, energetic treatment which in anyevent improves many of the symptoms associatedwith the Plummer-Vinson syndrome should beinstituted in all cases.

Endoscopic examination of the cesophagus isessential in all patients, and for three reasons:(i) to exclude other causes of the dysphagia;(2) to exclude any malignant change in thecesophagus; and (3) therapeutically to improvethe dysphagia which is often severe and dis-tressing. Even apparently innocent lesions shouldbe biopsied. In one of our patients carcinoma ofthe tongue was discovered on biopsy of a non-indurated superficial ulceration.

Because of the risk of the development ofcancer, all patients with the Plummer-Vinsonsyndrome should be kept constantly under reviewso that if malignant change occurs, early diagnosisand treatment can be instituted.

SummaryIt is now reasonably evident that the changes

observed in patients with Plummer-Vinson syn-drome (or sideropenic dysphagia) are caused by along-standing depletion of body iron stores.The evidence for this is, firstly, the diminishedmarrow and serum content of iron, and secondly,the observed retrogression of many of the classicalfeatures of the disease following the therapeuticadministration of iron. It is important to realizethat anwmia may be absent, even in long-standingdisease.

Invariably there are atrophic mucous mem-brane changes present throughout the uppergastro-intestinal tract and, in the early stages ofthe disease, these changes are reversible withiron administration. However, in the absence oftreatment, these mucosal changes become irre-versible and, in many patients, malignant de-generation occurs. This malignant change canoccur not only at hypopharyngeal level but atany or multiple sites in the mouth, tongue,pharynx or cesophagus.

Diagnosis should be possible before these irre-versible changes have occurred and, at this stage,the later malignant changes can be prevented bycontinued replenishment of the iron stores. Iflong-standing disease is present, the possibilityof later malignant change must be borne in mindso that early diagnosis and treatment can beinstituted.

September I96 I532by copyright.


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September I96I WATTS: The Importance of the Plummer-Vinson Syndrome 533

I wish to thank Professor M. R. Ewing for assistancein the preparation of this paper and Professor R. R. H.Lovell and Dr. J. Stubbe for permission to publishdetails of patients under their care.

I also acknowledge the assistance of Dr. N. A. Daviswith the pathology, and Miss C. J. McCall and Mrs.J. C. Higginbottom of the Central Cancer Registry,Melbourne for the statistics included in Table i.

REFERENCESAHLBOM, H. E. (1936): Simple Achlorhydric Anemia, Plummer Vinson Syndrome and Carcinoma of the Mouth.

Pharynx and Oesophagus in Women, Brit. med. J., ii, 331.AHLBOM, H. E. (I937)' Pradisponierende Faktoren fur plattenepithelkarzinom in mund, hals und speiserohre Eine

statistische untersuchungam material des Radiumhemmets, Stockholm. Acta radiol (Stockh.), x8, I63.ANDERSSON, N. S. E. (1950): Experimental and Clinical Investigations into the Effect of Parenterally Administered Iron,

Acta. med. scand. Supp., 90, 380.BEUTLER, E. (1957): Iron Enzymes in Iron Deficiency: Cytochrome C, J. clin. Invest., 36, 874.

(1959): Iron Enzymes in Iron Deficiency: Aconitase Activity and Citrate Metabolism, J. clin. Invest., 38, I605.BROWN KELLY, A. (I919): Spasm at the Entrance to the (Esophagus, J. Laryng, 34, 285.DEMULDER, R. (1958): Iron, A.M.A. Arch. intern. Med., 102, 254.HoovER, W. B. (I935): The Syndrome of Anemia, Glossitis and Dysphagia; New Engl. Y. Med., 213, 394.HURST, A. F. (1926): The Plummer-Vinson Syndrome (Spasm of the Pharyngo-(Esophageal Sphincter with Anaemia,

and Splenomegaly), Guy's Hosp. Rep., 76,426.JOHNSON, R. S. (193I): In discussion on ' Obstruction of the Upper End of the (Esophagus ', Proc. roy. Soc. Med.

24, I 206.Lancet (I960): Leading Article, ii, 27.LEES, F., and ROSENTHAL, F. D. (1958): Gastric Mucosal Lesions Before and After Treatment in Iron Deficiency

Anlmia, Quart. J. Med., 27, I9.LINDVALL, N. (1953): Hypopharyngeal Carcinoma in Sideropenic Dysphagia, Acta radiol. (Stockh.), 39, 17.LOGAN TURNER, A. (1913): Malignant Disease of the (Esophagus with Special Reference to Carcinoma of the Upper

End: a Clinical Study based upon an Analysis of 68 cases of Tumour, J. Laryng., 28, 281.(1920): Carcinoma of the Post Cricoid Region and Upper End of the (Esophagus, Ibid., 35, 34.

PATERSON, D. R. (I9I9): A Clinical Type of Dysphagia, Ibid., 34, 289.RAWSON, A., and ROSENTHAL, F. D. (I960): The Mucosa of the Stomach and Small Intestine in Iron Deficiency,

Lancet, i, 730.SAVILAHTI, M. (1946): On the Pathologic Anatomy of the Plummer Vinson Syndrome, Acta med. scand., 125, 40.SUZMAN, M. M. (I933): Syndrome of Anemia, Glossitis and Dysphagia, Arch. intern. Med., 51, I.VIDBOEK, A. (1944): Solitary and Multiple Carcinomas of the Upper Alimentary Tract, Acta Radiol., 25, 339.VINSON, P. P. (1922): Hysterical Dysphagia, Minn. Med., 5, IO7.WALDENSTROM, J. (1938): Iron and Epithelium: some Clinical Observations, Acta med. scand., SuPP. 90, 380.-- and KJELLBERG, S. R. (1939): The Roentgenological Diagnosis of Sideropenic Dysphagia, Acta radiol., 2o, 6i8.WARBURG, 0. (1956): On the Origin of Cancer Cells, Science, 123, 309.WEISBERGER, D. (1957): Precancerous Lesions, Y. Amer. dent. Ass., 54, 507.WITTS, L. J. (1931): The syndrome of Glossitis, Dysphagia and Anxmia, Guy's Hosp. Rep., 8i, 193.WYNDER, E. L., HULTBERG, S., JACOBSSON, F., and BROSS, I. J. (1957): Environmental Factors in Cancer of the Upper

Alimentary Tract, Cancer (Philad.), 10, 470.and FRYER, J. H. (1958): Etiologic Considerations of Plummer Vinson (Paterson-Kelly) Syndrome, Ann. intern.Med., 49, IIO6.


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